title: Hematopoietic stem and progenitor cell migration after hypofractionated radiation therapy in a murine model.
abstract: OBJECTIVE
  To characterize the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs) within tumor microenvironment after radiation therapy (RT) in a murine, heterotopic tumor model.
  
  
  METHODS
  Lewis lung carcinoma tumors were established in C57BL/6 mice and irradiated with 30 Gy given as 2 fractions over 2 days. Tumors were imaged with positron emission tomography/computed tomography (PET/CT) and measured daily with digital calipers. The HSPC and myelomonocytic cell content was assessed via immunofluorescent staining and flow cytometry. Functionality of tumor-associated HSPCs was verified in vitro using colony-forming cell assays and in vivo by rescuing lethally irradiated C57BL/6 recipients.
  
  
  RESULTS
  Irradiation significantly reduced tumor volumes and tumor regrowth rates compared with nonirradiated controls. The number of CD133(+) HSPCs present in irradiated tumors was higher than in nonirradiated tumors during all stages of regrowth. CD11b(+) counts were similar. PET/CT imaging and growth rate analysis based on standardized uptake value indicated that HSPC recruitment directly correlated to the extent of regrowth and intratumor cell activity after irradiation. The BM-derived tumor-associated HSPCs successfully formed hematopoietic colonies and engrafted irradiated mice. Finally, targeted treatment with a small animal radiation research platform demonstrated localized HSPC recruitment to defined tumor subsites exposed to radiation.
  
  
  CONCLUSIONS
  Hypofractionated irradiation resulted in a pronounced and targeted recruitment of BM-derived HSPCs, possibly as a mechanism to promote tumor regrowth. These data indicate for the first time that radiation therapy regulates HSPC content within regrowing tumors.
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, Michigan; Radiation Oncology, William Beaumont Health System, Royal Oak, Michigan.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kane
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Krueger
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dilworth
authors.forename: John T
authors.initials: JT
authors.lastname: Torma
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
authors.forename: Brian
authors.initials: B
authors.lastname: Marples
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Madlambayan
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D039481:CD11b Antigen / Q000032:analysis; D018827:Carcinoma, Lewis Lung / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology* / Q000532:radiotherapy; D002465:Cell Movement / Q000502:physiology / Q000528:radiation effects*; D002470:Cell Survival; D019583:Dose Fractionation, Radiation; D006023:Glycoproteins / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects*; D006657:Histones / Q000032:analysis; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064847:Multimodal Imaging / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology*; D010455:Peptides / Q000032:analysis; D049268:Positron-Emission Tomography; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden / Q000528:radiation effects
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D039481:CD11b Antigen; D006023:Glycoproteins; D006657:Histones; D010455:Peptides; C000606024:Prom1 protein, mouse; C475961:gamma-H2AX protein, mouse